Pattern of Kvβ Subunit Expression in Macrophages Depends upon Proliferation and the Mode of Activation

Abstract

Voltage-dependent potassium channels (Kv) in leukocytes are involved in the immune response. In bone marrow-derived macrophages (BMDM), proliferation and activation induce delayed rectifier K+ currents, generated by Kv1.3, via transcriptional, translational, and posttranslational controls. Furthermore, modulatory Kv beta subunits coassociate with Kv alpha subunits, increasing channel diversity and function. In this study we have identified Kv beta subunits in mouse BMDM, studied their regulation during proliferation and activation, and analyzed K+ current parameters influenced by these proteins. BMDM express all isoforms of Kv beta1 (Kv beta1.1, Kv beta1.2, and Kv beta1.3) and Kv beta2 (Kv beta2.1), but not Kv beta4, the alternatively spliced murine Kv beta3 variant. M-CSF-dependent proliferation induced all Kv beta isoforms. However, LPS- and TNF-alpha-induced activation differentially regulated these subunits. Although LPS increased Kv beta1.3, reduced Kv beta1.2, and maintained Kv beta1.1 mRNA levels constant, TNF-alpha up-regulated Kv beta1.1, down-regulated Kv beta1.2, and left Kv beta1.3 expression unchanged. Moreover, in contrast to TNF-alpha, M-CSF- and LPS- up-regulated Kv beta2.1. K+ currents from M-CSF- and LPS-stimulated BMDM exhibited faster inactivation, whereas TNF-alpha increased tau values. Although in M-CSF-stimulated cells the half-inactivation voltage shifted to more positive potentials, the incubation with LPS and TNF-alpha resulted in a hyperpolarizing displacement similar to that in resting BMDM. Furthermore, activation time constants of K+ currents and the kinetics of the tail currents were different depending upon the mode of activation. Our results indicate that differential Kv beta expression modifies the electrical properties of Kv in BMDM, dependent upon proliferation and the mode of activation. This could determine physiologically appropriate surface channel complexes, allowing for greater flexibility in the precise regulation of the immune response.